In our ongoing studies to identify the mechanisms through which cannabinoids alter brain function, we have begun collaborating with the Designer Drug Research Unit (DDRU) at the NIDA Intramural Research Program, to compare the pharmacological effects of designer cannabinoids with those of conventional natural cannabinoids such at delta-9-tetrahydrocannabinol (delta-9-THC), found in the marijuana plant. Designer cannabinoids are psychoactive molecules that are often marketed as incense, spice or other plant-related formulations. The psychoactive components of these drugs are typically synthesized in clandestine laboratories by amateur chemists, and in most cases structurally resemble cannabinoid molecules. The synthetic cannabinoids are made in bulk and sprayed onto plant material. The fact that these molecules are made in illicit laboratories without regulatory control often leads to exposure to adulterants and contaminants that can result in unintended toxicity. In addition, the structure of these synthetic cannabinoids is such that they have stronger effects, and longer durations of action at the same cannabinoid receptors that are activated by delta-9-THC. Although many of these drugs are widely consumed, their safety is generally untested, and their complete pharmacological sites of action remain unknown. The illicit nature of these compounds and their incompletely understood pharmacological actions has resulted in a large increase in world-wide emergency room visits by individuals using these drugs. Our initial studies have examined 3 compounds that were isolated from material seized by the U.S. Drug Enforcement Agency (DEA), and subsequently synthesized by professional chemists. These studies show that the compounds AM-2201, and XLR-11 are full agonists at CB1 receptors that inhibit glutamate release in the hippocampus. This is in contrast to delta-9-THC, which purportedly acts as a partial agonist, demonstrating approximately one-half of the ability to inhibit glutamate responses as the synthetic molecules. In addition, these synthetic cannabinoids were much more potent than delta-9-THC on this measure. Another compound that we tested, known as JWH-018, was also more efficacious than delta-9-THC, but less potent than the other 2 synthetic compounds. Our general conclusion thus far is that the synthetic cannabinoids can bind to the cannabinoid CB1 receptor with much greater potency and efficacy than delta-9-THC. We predict that this will lead to a much greater inhibition of neurotransmitter release, and a greater disruption of hippocampus-dependent cognition, and perhaps result in much higher levels of anxiety in humans. Additionally, these pharmacological properties of the synthetic cannabinoids would result in much longer durations of action, compared to delta-9-THC, because of the higher potency. Ongoing studies are designed to look for off site effects of these compounds at non-cannabinoid receptor targets in the brain. Currently, we are evaluating potential interactions of these ligands with serotonin type 1 receptors in the cerebral cortex, as well as at calcium-activated potassium channels in the nucleus accumbens in rat brain slices. Preliminary data suggest that there may be actions of these synthetic cannabinoids at other molecular sites in the CNS.